ANTIMICROBIAL CHEMOTHERAPY
DR. MEDHAT A. ELDAKER
Lecturer of Microbiology & Immunology
Faculty of Medicine – Mansoura University
1/4/2011 10:16:17 AM 2Dr. Medhat A. Eldaker
Antibacterial AgentsDesired properties of antibiotics:
1. Selective toxicity.
2. Bactericidal > bacteristatic.
3. Do not develop antibacterial resistance.
4. Broad spectrum.
5. Non-allergic.
6. Long plasma half-life.
7. Water soluble and stable.
8. Good tissue distribution (BBB-PBP).
1/4/2011 10:16:17 AM 3Dr. Medhat A. Eldaker
Antimicrobial Agents
Def:
In-vivo (Selective toxicity):
Antibacterial (Antibiotics)
Antifungal
Antiviral
In-vitro:
Antiseptics
Disinfectant
1/4/2011 10:16:17 AM 4Dr. Medhat A. Eldaker
Antibacterial Agents
Mechanism of action:
Cell wall synthesis.
Cell membrane function.
Protein synthesis.
DNA replication.
Other.
1/4/2011 10:16:17 AM 5Dr. Medhat A. Eldaker
Cell Wall Inhibitors
I. Lactam antibiotics
II. Glycopeptides
III. Polypeptides
1/4/2011 10:16:17 AM 6Dr. Medhat A. Eldaker
Cell Wall Inhibitors
I. Lactam antibiotics
1. Penicillin
2. Monobactam
3. Carbapenem
4. Cephalosporins
1/4/2011 10:16:17 AM 7Dr. Medhat A. Eldaker
Cell Wall InhibitorsI. Lactam antibiotics - Penicillin
A) Classic penicillin:Gram positive (Except S. aureus).
- Penicillin G & V. - Procaine Penicillin.
- Benzile penicillin.
B) Penicillinase resistant penicillin: S. aureus.
- Oxacillin. - Cloxacillin. - Flucloxacillin.
- Amoxycillin/Clavulinic acid - Ampicillin/Sulbactam.
C) Broad spectrum penicillins:Gram-negative (Except Pseudomonas).
- Ampicillin. - Amoxycillin.
- Carbenicillin. - Ticarcillin.
D) Ureidopenicillins: Pseudomonas.
-Piperacillin. - Mezlocillin. - Azlocillin.
1/4/2011 10:16:17 AM 8Dr. Medhat A. Eldaker
Cell Wall Inhibitors
I. Lactam antibiotics - Monobactam
Aztreonam (Azactam):
- Resistant Gram-negative bacteria.
- Pseudomonas.
I. Lactam antibiotics - Carbapenem
Imipenem (Tinam)
- Resistant Gram-negative & Gram-positive bacteria.
- Pseudomonas.
1/4/2011 10:16:17 AM 9Dr. Medhat A. Eldaker
Cell Wall InhibitorsI. Lactam antibiotics - Cephalosporin
4th G3rd G2nd G1st G
+ve = -ve -ve > +ve+ve = -ve+ve> -ve
Pseudomonas √Pseudomonas X
CefipimeCefotaxime
Ceftriaxone
Ceftazidime
Cefoperazone
Cefizoxime
Cefoxitin
Cefamandole
Cefuroxime
Cefaclor
Cefonicid
Ceforamide
Cefotetan
Cephaloridin
Cephalothin
Cephalexin
Cephdroxil
Cefazolin
Cephradin
1/4/2011 10:16:17 AM 10Dr. Medhat A. Eldaker
Cell Wall Inhibitors
II. Glycopeptides
Vancomycin
- Resistant Gram-positive bacteria.
- MRSA.
A. Cycloserine
Cycloserine
- TB
B. Bacitracin
Bacitracin
- Diagnostic
- Topical
III. Polypeptides
1/4/2011 10:16:17 AM 11Dr. Medhat A. Eldaker
Cell Wall Inhibitors
Penicillins and cephalosporins
Bacitracin, Vancomycin and cycloserine
1/4/2011 10:16:17 AM 12Dr. Medhat A. Eldaker
Protein Synthesis Inhibitors
50 S30 S
ChloramphenicolMacrolideTetracyclinAminoglycoside
BothB-cidalB.staticB-cidal
Enteric feverGm +ve> -veSpir-Rick-Chla Gm –ve & Pseu
ChloramphenicolErythromycin
Azythromycin
Clindamycin
Oxytetracyclin
Doxycyclin
Gentamicin
Amikacin
Tobramyscin
Neomycin
Kanamycin
Streptomycin
1/4/2011 10:16:17 AM 13Dr. Medhat A. Eldaker
DNA Replication Inhibitors
I. Sulphonamides
Bactiristatic
UTI-Chemoprophylaxis
- e.g Trimethoprim.
II. Quinolones
Bactricidal
Broad spectrum
- Ofloxacin - Ciprofloxacin
- Gatifloxacin - Levofloxacin
- Nitrofurantoin (UTI)III. Rifampicin
Bactricidal
TB
Inhibition of precursor
Inhibition of RNA
polymerase
Inhibition of DNA
polymerase
1/4/2011 10:16:17 AM 14Dr. Medhat A. Eldaker
Cytoplasmic membrane Inhibitors
Polyenes
Bactiristatic
- Polymyxin B topical
- Amphotercin B antifungal
- Mitronidazole anaerobes
1/4/2011 10:16:17 AM 15Dr. Medhat A. Eldaker
Antibiotic Combination Def:
Synergism:
1+1= > 2
Cidal + Cidal
Antagonism:
1 + 1 = 0
Cidal + Static
Addition:
1 + 1 = 2
Static + Static
1- Sequential block of a metabolic pathway
2- One drug may enhance the uptake of the
other.
3- One drug may facilitate the entry of the
second drug.
4- Suicidal ring.
1/4/2011 10:16:17 AM 16Dr. Medhat A. Eldaker
Antibiotic Combination
Indications:
Serious microbial infections.
Resistant pathogens.
Mixed infection.
Disadvantages:
Side effects.
Antagonism (drug reaction).
Economic impacts.
1/4/2011 10:16:17 AM 17Dr. Medhat A. Eldaker
Antimicrobial chemoprophylaxis
I) prophylaxis in persons of normal susceptibility exposed to specific pathogen.
- Prophylaxis from Rheumatic fever by long acting Penicillin.
- Prophylaxis from meningitis by Rifampicin.
II) Prophylaxis in persons of increased susceptibility:
- Heart diseases.
- Respiratory diseases (Chronic).
- Recurrent urinary tract infections.
- Immunosuppressed host.
III) Surgical prophylaxis
1/4/2011 10:16:17 AM 18Dr. Medhat A. Eldaker
Mechanism:
Decreased permeability.
Inactivation.
Alteration of target site.
Alteration of metabolic pathway.
Alteration of metabolic enzymes.
Bacterial Resistance to Antimicrobial Drugs
1/4/2011 10:16:17 AM 19Dr. Medhat A. Eldaker
Bacterial Resistance to Antimicrobial Drugs
Origin of Drug Resistance
Genetic Non-genetic
Chromosomal Extra-chromosomal
Plasmids
Transposonos
1/4/2011 10:16:17 AM 20Dr. Medhat A. Eldaker
Chromosomal Resistance(Drug Resistant Mutants)
Mechanism:
Spontaneous mutation Altered target.
Rare.
Need the presence of antibiotic selective pressure
factor.
Low frequency of transmission.
Example:
P12 of 30 S ribosomal subunit R (Streptomycin)
1/4/2011 10:16:17 AM 21Dr. Medhat A. Eldaker
Plasmid Resistance(R Factor)
Mechanism:
Presence of R factor???
Enzymatic:
B lactamases
Acetyl transferase
No need for selective pressure factor.
High frequency of transmission by ???
- Plasmid carry genes of resistance.
- If transmissible epidimic
resistance
1/4/2011 10:16:17 AM 22Dr. Medhat A. Eldaker
Transposons Resistance(jumping genes)
Mechanism:
Presence of transposons ???
Enzymatic:
B lactamases
No need for selective pressure factor.
High frequency of transmission by ???
1/4/2011 10:16:17 AM 23Dr. Medhat A. Eldaker
Transposons & Plasmids(Extra chromosomal resistance)
= Resistance exchange
1/4/2011 10:16:17 AM 24Dr. Medhat A. Eldaker
Non-Genetic Resistance(Biochemical Resistance)
Mechanism:
Decreased permeability.
Alteration of target site.
Metabolic pathway.
Metabolic enzymes.
Characters:
Non transmissible.
1/4/2011 10:16:17 AM 25Dr. Medhat A. Eldaker
Antibacterial AgentsChoice of antibiotics:
1. Selective toxicity.
2. Bactericidal > bacteristatic.
3. Do not develop antibacterial resistance.
4. Broad spectrum.
5. Non-allergic.
6. Long plasma half-life.
7. Water soluble and stable.
8. Good tissue distribution (BBB-PBP).
Good Luck
DR. MEDHAT A. ELDAKER
Lecturer of Microbiology & Immunology
Faculty of Medicine – Mansoura University